2. Academic Validation
  3. Synthesis, biological evaluation, and docking studies of novel pyrrolo[2,3-b]pyridine derivatives as both ectonucleotide pyrophosphatase/phosphodiesterase inhibitors and antiproliferative agents

Synthesis, biological evaluation, and docking studies of novel pyrrolo[2,3-b]pyridine derivatives as both ectonucleotide pyrophosphatase/phosphodiesterase inhibitors and antiproliferative agents

  • Eur J Med Chem. 2021 May 5:217:113339. doi: 10.1016/j.ejmech.2021.113339.
Saif Ullah 1,  Mohammed I El-Gamal 2,  Randa El-Gamal 3,  Julie Pelletier 4,  Jean Sévigny 5,  Mahmoud K Shehata 6,  Hanan S Anbar 7,  Jamshed Iqbal 8
Affiliations

Affiliations

  • 1 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
  • 3 Department of Medical Biochemistry, Faculty of Medicine, University of Mansoura, Mansoura, 35516, Egypt.
  • 4 Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada.
  • 5 Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada; Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada.
  • 6 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 7 Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, 19099, United Arab Emirates. Electronic address: dr.hanan@dpc.edu.
  • 8 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan. Electronic address: drjamshed@cuiatd.edu.pk.
PMID: 33744686 DOI: 10.1016/j.ejmech.2021.113339
Abstract

Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) together with nucleoside triphosphate diphosphohydrolases (NTPDases) and alkaline phosphatases (APs) are nucleotidases located at the surface of the cells. NPP1 and NPP3 are important members of NPP family that are known as druggable targets for a number of disorders such as impaired calcification, type 2 diabetes, and Cancer. Sulfonylurea derivatives have been reported as antidiabetic and Anticancer agents, therefore, we synthesized and investigated series of sulfonylurea derivatives 1a-m possessing pyrrolo[2,3-b]pyridine core as inhibitors of NPP1 and NPP3 isozymes that are over-expressed in Cancer and diabetes. The enzymatic evaluation highlighted compound 1a as selective NPP1 inhibitor, however, 1c was observed as the most potent inhibitor of NPP1 with an IC50 value of 0.80 ± 0.04 μM. Compound 1l was found to be the most potent and moderately selective inhibitor of NPP3 (IC50 = 0.55 ± 0.01 μM). Furthermore, in vitro cytotoxicity assays of compounds 1a-m against MCF-7 and HT-29 Cancer cell lines exhibited compound 1c (IC50 = 4.70 ± 0.67 μM), and 1h (IC50 = 1.58 ± 0.20 μM) as the most cytotoxic compounds against MCF-7 and HT-29 Cancer cell lines, respectively. Both of the investigated compounds showed high degree of selectivity towards Cancer cells than normal cells (WI-38). Molecular docking studies of selective and potent Enzyme inhibitors revealed promising mode of interactions with important binding sites residues of both isozymes i.e., Thr256, His380, Lys255, Asn277 residues of NPP1 and His329, Thr205, and Leu239 residues of NPP3. In addition, the most potent antiproliferative agent, compound 1h, doesn't produce hypoglycemia as a side effect when injected to mice. This is an additional merit of the promising compound 1h.

Keywords

Antiproliferative activity; Molecular docking studies; NPP1 and NPP3; Pyrrolo[2,3-b]pyridine scaffold; Sulfonylurea.

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